Tofacitinib, 3-((3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)-3-oxopropionitrile, has the chemical formula C16H20N6O and the following structural formula

The term “tofacitinib” should be understood, unless otherwise indicated herein, to include any pharmaceutically acceptable form and salts of the compound. Tofacitinib may be present in a crystalline or amorphous form. Tofacitinib, salts of tofacitinib, methods for synthesizing tofacitinib, certain polymorphs of tofacitinib, and certain uses of tofacitinib are disclosed in WO01/42246, WO02/096909, and WO03/048162.
Tofacitinib is generally known to be useful as an inhibitor of protein kinases, such as the enzyme Janus Kinase (JAK) and as such are useful therapy as immunosuppressive agents for organ transplants, xeno transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, psoriatic arthritis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia and other indications where immunosuppression would be desirable.
Tofacitinib is being developed as an immediate release tablet form with doses ranging from 5 mg to 10 mg administered BID (two times a day). Tofacitinib, as the citrate salt of tofacitinib, is approved in the US under the brand XELJANZ™. Pharmaceutical dosage forms of tofacitinib are known and described in WO01/42246, WO02/096909, and WO03/048162. In addition, WO2012/100949 purports to describe a modified release formulation of tofacitinib. While WO2012/100949 mentions that tofacitinib might be formulated in a modified release formulation, desirable pharmacokinetic characteristics have not been disclosed.
While the commercial immediate release tablet dosage form provides efficacious blood levels of tofacitinib to subjects (dictated by the average blood plasma concentration of tofacitinib, Cave, over a 24 hour period), it may be possible to reduce the number of dosings to once daily (QD) with a sustained-release dosage form of tofacitinib while maintaining consistent therapeutic effect, thus enhancing convenience and potentially improving compliance.
Sustained-release dosage forms are typically designed to provide the longest possible duration of release, to minimize: 1) the fluctuations in blood plasma concentration during the dosing interval (i.e. the ratio of the maximum blood plasma concentration, Cmax,ss, to the minimum blood plasma concentration, Cmin,ss, during the dosing interval), and 2) the amount of drug required to achieve the desired therapeutic effect, for the purpose of improving the safety and tolerability profile. For example, WO2012/100949 purports to describe a modified release formulation of tofacitinib having the advantage that tofacitinib is gradually released over a relatively long period at a uniform concentration, which results in little blood level fluctuation in the patient.
However, it was surprisingly found that the bioavailability of tofacitinib is reduced as the duration of release is prolonged, thereby requiring increased amounts of tofacitinib to be administered in the sustained release dosage form to provide efficacious blood levels to subjects.
In addition, the pharmacokinetic profile of the BID immediate release tablets contains periods during a 24 hour time period beneath the IC50 for the JAK1/3 heterodimer signaling (“Drug Holiday”), due to the combination of total drug absorbed and the ratio of the maximum blood plasma concentration, Cmax,ss, to the minimum blood plasma concentration, Cmin,ss, during the dosing interval. Tofacitinib is a selective inhibitor of the Janus kinase (JAK) family of kinases with a high degree of selectivity against other kinases in the human genome. In kinase assays, tofacitinib inhibits JAK1, JAK2, JAK3, and to a lesser extent tyrosine kinase (TyK2). In cellular settings, where JAK kinases signal in pairs, tofacitinib preferentially inhibits cytokines that signal through JAK3 and/or JAK1 including interleukin (IL)-2, -4, -6, -7, -9, -15, -21, and type I and II interferons. These cytokines are pro-inflammatory and integral to lymphocyte function. Inhibition of their signaling may thus result in modulation of multiple aspects of the immune response. Over inhibition of signaling through JAK3 and/or JAK1 could compromise the body's immune system.
It was surprisingly found that the drug holiday period of tofacitinib relative to the IC50 for JAK1/3 signaling during a 24 time period is increased as the release duration from a sustained release dosage form is prolonged. As such, sustained release dosage forms, as described in the prior art, containing tofacitinib would not provide drug holiday periods comparable to the PK profile of the BID immediate release tablets, due to the reduced blood plasma concentrations of tofacitinib exhibited by sustained release dosage forms, as described by the prior art. Accordingly, it was surprisingly found that to provide the optimal PK profile (i.e. optimal exposure and optimal Cmax,ss/Cmin,ss ratio while avoiding elevated levels of the maximum blood plasma concentration) for once-daily administration of tofacitinib, dosage forms with shorter durations of sustained release are preferred. It was also surprisingly found that to minimize the total dose of tofacitinib administered to subjects while providing efficacious blood levels in subjects, dosage forms with shorter durations of sustained release are preferred.